As extrinsic AD is commonly seen, dermatologists feel its prevalence on their daily examination. On the other hand, the frequency of intrinsic AD has been a matter of investigation. Schmid-Grendelmeier et al. [19] summarized the 12 reports that had been published from 1990 to 2000 and documented the clinical features of extrinsic and intrinsic AD. According to their study, the frequency of intrinsic AD was 10–45%. More recently, the incidence of extrinsic AD and intrinsic AD was reported as follows: 73% vs 27% [22] and 63% vs 37% [18] in German children, 88% vs 12% in Hungarian adults [9], 78.2% vs 21.8% in Dutch patients at the age of 13–37 years [6], and approximately 80% vs 20% in Korean [23]. These data are in accordance with the empirical knowledge that about 20% of AD patients show normal IgE levels and lack of sensitization toward environmental allergens. The prevalence may depend on environment, as intrinsic AD was higher in incidence in East Germany than West Germany, although the exact reason is unknown [8].

While extrinsic AD equally affects both males and females, intrinsic AD shows female predominance [1, 6, 10, 15, 24]. Our observation disclosed that 76.5% of AD patients were female [14]. More extremely, 14 intrinsic AD patients enrolled in a study were all female [24].

Extrinsic AD starts at infancy or early childhood and may persist at adulthood with or without transient remission. The clinical course of intrinsic AD is an issue to be clarified. A Korean group of investigators showed that the intrinsic type is more prevalent in infancy, and even the third group of the indeterminate type between the intrinsic and extrinsic ones can be identified in younger generation [13]. A prospective birth cohort study followed for 5 years by a German group demonstrated that one third of child AD was the intrinsic one and more common in female [25]. Another German group indicated the low prevalence of the intrinsic AD among adult patients [7]. They showed 6.9% of patients fulfilled the criteria of intrinsic AD, and after follow-up, the incidence was declined to 5.4% because some patients developed respiratory allergies or IgE-mediated sensitizations. These observations may suggest that the intrinsic type is more prevalent in children than adults.

However, it should be careful that a considerable number of the above infantile or juvenile intrinsic AD patients possibly develop the extrinsic type as they grow and show high levels of serum IgE. Furthermore, the later onset was reported to be a feature of intrinsic AD [6]. It is tempting to speculate that the juvenile IgE-normal AD group contains two types, the genuine intrinsic AD and the IgE level-normal stage of extrinsic AD. In addition, as we see in Japanese patients with intrinsic AD, it may occur or deteriorate after high school age.

Transepidermal water loss (TEWL) and skin surface hydration (capacitance) are representative barrier assessments. Extrinsic AD patients have increased TEWL and decreased skin surface hydration compared to healthy subjects. Intrinsic AD patients have higher levels of TEWL and skin surface hydration than extrinsic AD [23]. On the antecubital fossae, however, both types of AD patients have higher TEWL and decreased capacitance. We examined the skin surface hydration and TEWL at the nonlesional forearm and lower leg of patients and normal volunteers in a comparison between the extrinsic and intrinsic types [14]. The level of skin surface hydration was significantly lower in extrinsic AD than in normal control subjects. Thus, the skin barrier function is impaired in extrinsic AD and relatively preserved in intrinsic AD. The barrier impairment may induce allergic responses to external antigen in extrinsic AD (Fig. 15.2).

The skin perception threshold of electric current stimuli is one of the indices of itch. The electric current perception threshold significantly correlates with the skin surface hydration and inversely with TEWL in intrinsic AD patients as well as healthy individuals. In contrast, extrinsic AD patients do not exhibit such a correlation. Therefore, intrinsic AD patients retain the normal barrier function and sensory reactivity to external pruritic stimuli [17]. We recently found that the frequency of sensitive skin is higher in extrinsic AD than in intrinsic AD.

It is well known that loss-of-function mutation in FLG is a risk factor for AD [26]. These mutations also represent a strong genetic predisposing factor for atopic eczema, asthma, and allergies in various countries [27]. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases, such as kallikrein-5 [28], to form monomeric FLG, which is further degradated into natural moisturizing factor. Perturbation of skin barrier function as a result of reduction or complete loss of FLG expression leads to enhanced percutaneous transfer of allergens (Fig. 15.2). The association of the FLG mutations in particular with the extrinsic type of AD was observed [15, 29].

Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD (Fig. 15.1), which represents a shared feature of AD and ichthyosis vulgaris (Fig. 15.1). This is in accordance with lower frequency of palmar hyperlinearity in the intrinsic type [6, 15]. We investigated FLG mutations in IgE-high and IgE-normal Japanese AD patients and found FLG mutations are less prevalent in the IgE-normal group [15, 21]. In the IgE-high patients, there was no statistical difference in SCORAD or IgE levels between the FLG mutation-bearing and FLG mutation-lacking patients. It has also been reported that FLG mutations predispose to early-onset and extrinsic AD [30]. Recently, we performed proteome analysis of extracts from stratum corneum of AD patients. The amounts of FLG were decreased in both extrinsic and intrinsic AD compared to healthy subjects, although the reduction tended to be more marked in extrinsic AD [31].

Although AD is a well-known Th2-polarized disease, there are some differences in systemic cytokine polarization between the two types of AD. In accordance with high serum IgE levels, extrinsic AD patients show high levels of Th2 cytokines, such as IL-4, IL-5, and IL-13, but intrinsic AD is linked with much lower levels of IL-4 and IL-13 [10]. Along with the elevation of IL-5 [32, 33], eosinophil counts [13] and eosinophil cationic protein levels [22] are increased in extrinsic AD. Meanwhile, there was a report demonstrating that both extrinsic and intrinsic patients had increased production of IL-5 and IL-13 [34]. However, when peripheral blood mononuclear cells were stimulated with anti-CD3 antibody, extrinsic AD patients had a decreased capacity to produce IFN-γ and GM-CSF as compared to the intrinsic AD [35]. The apoptosis of circulating memory/effector Th1 cells is confined to extrinsic AD patients, whereas intrinsic AD patients show no evidence for enhanced T-cell apoptosis in vivo [35].

Circulating IFN-γ⁺ T-cell frequency was higher in intrinsic than extrinsic AD in our study [15]. Although not statistically significant, there was a tendency that the frequencies of circulating IL-4⁺ or IL-5⁺ Th2 cells were higher in extrinsic AD than in intrinsic AD. Intrinsic AD has a less Th2-skewing state but has a relatively high Th1 state, as assessed by IFN-γ-producing T cells (Fig. 15.3). The overproduction of IFN-γ may further downregulate IgE production in intrinsic AD, as suggested by our in vitro study [15].

In the skin lesions, eosinophils infiltrate in the dermis more markedly in extrinsic than intrinsic AD, and extrinsic AD exhibits more prominent deposition of eosinophil granular protein and higher staining for eotaxin [12, 36]. Although the levels of mRNA expression for IL-5, IL-13, and IL-1β are higher in both types of AD patients than nonatopic subjects, extrinsic AD shows even higher levels than intrinsic AD [36]. The expression of IFN-γ, IL-12, GM-CSF, IL-4, and IL-10 is elevated without differences between the extrinsic and intrinsic AD [35]. In the lesional skin, however, higher activation of all inflammatory axes, including Th2, was seen in intrinsic AD [37], suggesting an important role of Th2 cells in the development of intrinsic AD lesions as well as extrinsic AD lesions.

We demonstrated that Th17 cells, producing IL-17A and IL-22, increased in the peripheral blood of AD and Th17 cells infiltrated in the acute skin lesions more markedly than in the chronic lesions [38]. There was a tendency that the frequency of circulating Th17 cells was higher in intrinsic AD than in extrinsic AD [15]. In the lesional skin, another group of investigators reported that positive correlations between Th17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and Th2 cytokine (IL-4 and IL-5) levels [37]. In AD, the acute skin lesion corresponds to the late phase reaction evoked by Th2 cells and eosinophils, while the chronic skin lesion corresponds to the delayed-type hypersensitivity induced by Th1/Tc1 cells [39]. Since Th17 cells exist already in the Th2-associated acute lesions, they seem to gradually disappear in the progression to the chronic lesion where Th1/Tc1 cells infiltrate.

Both extrinsic and intrinsic types show high serum concentration levels of Th2 chemokines, CCL17/TARC and CCL22/MDC, and high peripheral blood mononuclear cell expression of CCL17 and CCL22 at comparable levels [40]. We found that both groups had higher levels of serum CCL17 than healthy control; however, its value was significantly higher in extrinsic than intrinsic AD [15, 38]. The blood levels of soluble receptors derived from lymphocytes correlate with the activity in various diseases. There is no significant difference in the elevated amounts of sCD23, sCD25, and sCD30 between the two types [41].

An earlier study showed that extrinsic AD is characterized by a significantly high level of the expression of IgE high-affinity receptor (FCεR) on the CD1a⁺ DCs compared to intrinsic AD [1, 42]. When the high-affinity/low-affinity expression ratio was used as a disease marker for AD, the values for intrinsic AD fall below the diagnostic cutoff level, suggesting that intrinsic AD can be distinguished by phenotyping of epidermal LCs [1, 42]. In accordance with these data from the lesional skin, the surface expression of the high- and low-affinity receptor for IgE and the IL-4Rα chain is significantly elevated in circulating monocytes from extrinsic AD patients [3].

It is possible that epidermal LCs in the barrier-disrupted skin produce high amounts of Th2- and eosinophil-attracting chemokines. Recent accumulating evidence indicates that upon external stimulation, such as scratching and proteinases, epidermal keratinocytes produce thymic stromal lymphopoietin (TSLP), which stimulates LCs possessing TSLP receptors to promote Th2-mediated responses (Fig. 15.3) [43]. Moreover, TSLP directly stimulates Th2 cells bearing TSLP receptor to release IL-4, which leads to a vicious cycle [44]. Protein antigen is more essential than hapten as the cause of extrinsic AD. Upon epicutaneous application of ovalbumin (OVA), conditional LC depletion attenuated the development of clinical manifestations as well as serum OVA-specific IgE increase, OVA-specific T-cell proliferation, and IL-4 mRNA expression in the draining lymph nodes [45]. Consistently, even in the steady state, permanent LC depletion resulted in decreased serum IgE levels, suggesting that LCs mediate the Th2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization [45]. Thus, LCs initiate epicutaneous sensitization with protein antigens and induce Th2-type immune responses via TSLP signaling, suggesting that LCs play a mandatory role in extrinsic AD. In this scenario, the additional but powerful direct effect of TSLP on Th2 cells further exaggerates the response [44].